Submissions for variant NM_016955.4(SEPSECS):c.114+3A>G

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV001281617	SCV001468946	likely pathogenic	not provided		criteria provided, single submitter	clinical testing
Invitae	RCV001281617	SCV002190740	pathogenic	not provided	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the SEPSECS gene. It does not directly change the encoded amino acid sequence of the SEPSECS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs748528138, gnomAD 0.02%). This variant has been observed in individuals with SEPSECS-related conditions (PMID: 34234304, 35012964; Invitae). ClinVar contains an entry for this variant (Variation ID: 984624). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV003387987	SCV003920815	pathogenic	Pontocerebellar hypoplasia type 2D	2023-04-27	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323838	SCV004029171	likely pathogenic	Pontoneocerebellar hypoplasia	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: SEPSECS c.114+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. In addition, at least one minigene splicing assay revealed this variant results in skipping of exon 1 (Schlter_2022). However, one splicing assay reported cDNA sample from blood cells does not observe alteration in the splicing (Arrudi-Moreno_2021). The variant allele was found at a frequency of 4.6e-05 in 151924 control chromosomes (gnomAD). c.114+3A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Pontocerebellar Hypoplasia, Type 2D, inherited ataxia or genetic white matter disorders (Benkirane_2021, Arrudi-Moreno_2021, Schlter_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 32555262, 35155316, 35012964, 36085396, 31748115). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264723	SCV001442954	uncertain significance	Neurodevelopmental abnormality	2020-08-14	no assertion criteria provided	clinical testing